We have studied 28 patients with systemic lupus erythematosus, 5 of whom had a lupus anticoagulant, as well as 10 normal individuals. All 5 lupus anticoagulant patients had antibodies reactive against anionic phospholipids (PS,PA,PI); none of the other patients or normals showed such reactivity (although several patients had antibodies to cardiolipin). Antibodies were isolated from several patient plasmas using either a PS-PA-Sepharose affinity column (synthesized in our laboratory) or using PA, PS or PI liposomes. In several cases the eluted antibodies showed surprisingly restricted heterogeneity on isoelectric focusing. In 4 of the 5 lupus anticoagulant patients the inhibitory effect of the antibodies was not present when washed platelets were substituted for phospholipids in coagulation tests; in the 5th patient washed platelets first had to be treated with calcium-ionophore. Thus it appears that the mechanism of the lupus anticoagulant is a general one and consists of the presence of antibodies to anionic phospholipids which interfere with calcium dependent binding of gla-containing coagulation factors to anionic phospholipid micelles.